PGC1a Suppresses Prostate Cancer Cell Invasion through ERRa Transcriptional Control

The PPARγ coactivator 1 alpha (PGC1α) is a prostate tumor suppressor that controls the balance between anabolism and catabolism. PGC1A downregulation in prostate cancer is causally associated with the development of metastasis. Here we show that the transcriptional complex formed by PGC1α and estrog...

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Detalles Bibliográficos
Autores: Valcárcel Jiménez, Lorea, Macchia, Alice, Crosas Molist, Eva, Schaub Clerigué, Ariane, Camacho Soguero, Laura, Martín Martín, Natalia, Cicogna, Paolo, Viera Bardón, Cristina, Fernández Ruiz, Sonia, Rodríguez Hernández, Irene, Hermanova, Ivana, Astobiza Pérez, Janire, Cortázar, Ana Rosa, Corres Mendizabal, Jon, Gómez Muñoz, Antonio, Sanz Moreno, Victoria, Torrano Moya, Verónica, Carracedo Pérez, Arkaitz
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/78482
Acceso en línea:http://hdl.handle.net/10810/78482
Access Level:acceso abierto
Palabra clave:prostate cancer
metabolism
PGC1a
ERRA
invasion
Descripción
Sumario:The PPARγ coactivator 1 alpha (PGC1α) is a prostate tumor suppressor that controls the balance between anabolism and catabolism. PGC1A downregulation in prostate cancer is causally associated with the development of metastasis. Here we show that the transcriptional complex formed by PGC1α and estrogen-related receptor 1 alpha (ERRα) controls the aggressive properties of prostate cancer cells. PGC1α expression significantly decreased migration and invasion of various prostate cancer cell lines. This phenotype was consistent with remarkable cytoskeletal remodeling and inhibition of integrin alpha 1 and beta 4 expression, both in vitro and in vivo. CRISPR/Cas9-based deletion of ERRα suppressed PGC1α regulation of cytoskeletal organization and invasiveness. Mechanistically, PGC1α expression decreased MYC levels and activity prior to inhibition of invasiveness. In addition, PGC1α and ERRα associated at the MYC promoter, supporting the inhibitory activity PGC1α. The inverse correlation between PGC1α–ERRα activity and MYC levels was corroborated in multiple prostate cancer datasets. Altogether, these results support that PGC1α–ERRα functions as a tumor-suppressive transcriptional complex through the regulation of metabolic and signaling events.

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